Tofacitinib inhibits CD4 T cell polarisation to Th1 during priming thereby leading to clinical impact in a model of experimental arthritis

Bejad, M., Bonilha, C. S., McInnes, I. B. , Garside, P. and Benson, R. A. (2022) Tofacitinib inhibits CD4 T cell polarisation to Th1 during priming thereby leading to clinical impact in a model of experimental arthritis. Clinical and Experimental Rheumatology, 40(7), pp. 1313-1323. (doi: 10.55563/clinexprheumatol/4rqeg0) (PMID:34494958)

Abstract

Objectives: Janus kinases (JAK) are key cell membrane orientated tyrosine kinases that regulate inflammatory responses by transducing signals received by cytokine receptors that directly influence the polarisation and function of Th cells. Tofacitinib is a pan-JAK inhibitor approved for the treatment of RA. In this study, we explored the effects of tofacitinib in the outcomes of CD4+ T cell-dendritic cell (DC) interactions and their impact in autoimmune arthritis. Methods: The impact of tofacitinib in CD4+ T cell outcomes during priming or re-activation were analysed using antigen-specific in vitro and/or in vivo systems. A breach of self-tolerance model of arthritis was used to investigate the effects of tofacitinib in the outcomes of newly primed and antigen experienced CD4+ T cells. Results: Tofacitinib inhibited Th1 polarisation during priming both in vitro and in vivo. In vitro, impaired T-bet expression and IFN-y production persisted upon secondary antigen challenge. Tofacitinib treatment during re-activation in vitro did not impact differentiation of antigen experienced CD4+ T cell towards Th1 phenotype. Moreover, JAK inhibition limited adaptive immune responses mediated by recently activated T cells and subsequent breach of self-tolerance in experimental arthritis. Conclusions: Our findings provide a novel mode of action for tofacitinib, demonstrating a potential therapeutic utility via homeostatic immune restoration in very early autoimmune arthritis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McInnes, Professor Iain and Benson, Dr Robert and Garside, Professor Paul and Bonilha, Mr Caio
• Authors: Bejad, M., Bonilha, C. S., McInnes, I. B., Garside, P., and Benson, R. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Clinical and Experimental Rheumatology
• Publisher: Pacini Editore Srl
• ISSN: 0392-856X
• ISSN (Online): 1593-098X
• Published Online: 07 September 2021
• Copyright Holders: Copyright © 2021 Clinical and Experimental Rheumatology
• First Published: First published in Clinical and Experimental Rheumatology 40(7): 1313-1323
• Publisher Policy: Reproduced with the permission of the Publisher

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
303229		RACE Renewal	Iain McInnes	Versus Arthritis (ARTRESUK)	NW/22072	III - Immunology
166480		Defining the Role of Cell Migration in the Initiation and Regulation of Pathogenesis in Inflammatory Arthritis	Paul Garside	Versus Arthritis (ARTRESUK)	MP/19788	III - Immunology